Malignant mesothelioma is a disease of growing importance. Its incidence is increasing as a result of the widespread use of its major etiologic agent, asbestos exposure, which is implicated in 70 to 80% of patients. The ubiquitous presence of asbestos, from schools to shipyards, has generated great public concern and awareness of this disease. Malignant mesothelioma is uniformly fatal, and neither surgery nor radiotherapy is curative. Very little information is available regarding the activity of chemotherapeutic agents. It is unlikely that empirical clinical trials will lead to any breakthrough in this disease. The availability at Mount Sinai of two distinct cell lines of human malignant mesothelioma serially transplanted into nude mice for over 4 years is unique. These two lines have retained the original pathological, histochemical and ultrastructural features despite serial transplantation. Karotypes have confirmed their human nature. This model will allow the screening of many classic and newer agents, alone and in combination, a task which would be impossible to conduct clinically even for cooperative groups, in view of the still relatively small number of patients with mesothelioma. An attempt at establishing new lines of mesothelioma representing the histologic spectrum of the disease (epithelial, mesenchymal and mixed) as well as different histochemical features, (high and low production of hyaluronic acid) will be investigated. Preliminary results in this nude mouse system have revealed that mitomycing C in one line, and cisplatin in the other one, were the most active single agents. The combination of mitomycin C and cisplatin, however, has been so far the most active regimen for both lines of human malignant mesothelioma xenografts in nude mice. Based entirely on these experiments, a clinical trial of mitomycin C and cisplatin for patients with malignant mesothelioma was begun at Mount Sinai, a referral center with probably the highest single institutional accrual for this disease in the United States. Initial clinical results of this combination strongly suggest that the nude mouse model does have predictive value in this system. The experimental nude mouse model, strengthened by the availability of an appropriate clinical setting, will allow further research to select regimens effective in nude mice bearing human mesothelioma xenografts, to correlate them with cell types and histochemical features, and to evaluate the most active ones in patients, in an effort to determine the predictiveness of the nude mouse model and to discover new effective therapies for mesothelioma.